Decoding neuronal activity history at the genome through the spatially segregated inducible transcription factors.

通过空间分离的诱导转录因子解码基因组中的神经元活动历史。

• 批准号: 10244737
• 负责人: Gian-Stefano Brigidi
• 金额: $ 137.25万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-15 至 2023-08-01
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10244737
• 关键词: Award; Behavior; Behavioral; Brain; Cell Nucleus; Cells; DNA-Binding Proteins; Gene Expression; Gene Expression Regulation; Genes; Genome; Genomics; Hippocampus (Brain); Learning; Link; Mediating; Memory; Modification; Mus; Neurons; Output; Pathway interactions; Phenotype; Process; Property; Recording of previous events; Regulation; Reporting; Signal Transduction; Stimulus; Synapses; Synaptic plasticity; Thinking; Update; cell type; extracellular; flexibility; in vivo; innovation; interest; neural circuit; programs; response; synaptic function; tool; transcription factor

Project Summary/Abstract: During learning, task-relevant neurons convert transient activity signals into stable modifications of their synaptic properties in order to alter their output and support memory formation, a process broadly called plasticity. The most enduring forms of plasticity require regulation of the genome. Inducible transcription factors (ITFs) are a subset of rapidly induced, activity-dependent genes that support plasticity by triggering downstream programs of gene expression that directly impact neuronal functions. Indeed, ITFs have been used as tools to track task- relevant neurons in vivo during behavior, and intensive efforts in the field have uncovered mechanisms that link diverse extracellular stimuli and depolarizing activity to ITF expression in neurons. Despite this long-standing interest in ITFs, a wide gap has emerged in the study of their neuronal functions: What features of neuronal activity do ITFs communicate to the nucleus? Can they regulate the genome in distinct ways in response to different forms of activity? Does ITF-mediated gene regulation support synaptic and behavioral adaptations tailored to the activity history of the cell? Answering these questions requires a shift of the status quo away from thinking of ITF expression as a generalized response to neuronal activity. This proposal presents the innovative hypothesis that the genome decodes learning rules to support synaptic plasticity through activity-reporting ITF expression pathways. This project establishes a discovery pipeline that will reveal genomic mechanisms underlying neural circuit plasticity by first profiling activity-dependent ITF expression mechanisms in the murine hippocampus, and then mapping and manipulating ITF target genes to determine their impact on local synapse functions. The results of this project have the potential to dramatically expand the repertoire of intracellular signaling and genomic mechanisms available to neurons and other excitable cell types to flexibly update their functions and phenotypes in response to extracellular stimuli.

项目概要/摘要： 在学习过程中，任务相关的神经元将短暂的活动信号转化为突触的稳定修饰， 为了改变它们的输出和支持记忆的形成，一个广泛称为可塑性的过程。的 最持久的可塑性形式需要基因组的调节。诱导转录因子（ITFs）是一种 通过触发下游程序支持可塑性的快速诱导的活性依赖性基因的子集 直接影响神经元功能的基因表达。事实上，ITF已被用作跟踪任务的工具， 相关的神经元在体内的行为，并在该领域的密集努力已经发现的机制， 不同的细胞外刺激和去极化活性对神经元ITF表达的影响。尽管这种长期的 尽管人们对ITFs很感兴趣，但在对其神经元功能的研究中出现了很大的差距：神经元的功能是什么？ ITF与细胞核的通讯活动？它们能以不同的方式调节基因组， 不同形式的活动？ITF介导的基因调控支持突触和行为适应吗 根据细胞的活动历史定制的？解决这些问题需要改变现状， 认为ITF表达是对神经元活动的普遍反应。该提案提出了创新的 假设基因组解码学习规则，通过活动报告ITF支持突触可塑性 表达途径。该项目建立了一个发现管道，将揭示基因组机制 通过首次分析小鼠中活性依赖性ITF表达机制的潜在神经回路可塑性 海马，然后映射和操纵ITF靶基因，以确定它们对局部突触的影响 功能协调发展的该项目的结果有可能大大扩大细胞内的所有功能， 神经元和其他可兴奋细胞类型可利用的信号传导和基因组机制，以灵活地更新它们的 功能和表型响应细胞外刺激。